Airway remodeling is an irreversible process that contributes to development and progression of asthma. Repetitive injury to the airways from various causes may be a participating factor in airway remodeling. Recent studies have shown that ozone-induced oxidative injury causes chronic airflow obstruction, possibly due to airway remodeling. Therefore, oxidative injury from environmental or other sources may participate in airway remodeling. Preliminary data from our laboratory suggests that osteopontin (OPN), a cytokine involved in tissue repair and remodeling, may have a role in oxidative injury. In the proposed research plan, I will test the hypothesis that OPN produced in response to ozone-induced oxidative injury causes airway remodeling in humans, particularly in those with asthma. Using parallel ozone exposure experiments in humans and OPN-deficient mice, I will first determine whether OPN is involved in recruitment of macrophages into airways after oxidative injury in subjects with asthma (Aim 1). Second, I will determine whether OPN is involved in airway remodeling after oxidative injury in subjects with asthma (Aim 2). Finally, I will investigate the mechanistic role of OPN in ozone-induced oxidative injury in asthmatic lungs (Aim 3). In addition, the microarray gene expression study proposed in Aim 3 of the study will help to identify other inflammatory molecules that may be important in airway remodeling due to oxidative injury. This work promises to yield important insights into the fundamental biology of oxidative injury and its role in airway remodeling as well as elucidating the function of OPN in airway inflammation and injury. Understanding the mechanisms underlying airway remodeling is an important step in creating new strategies for prevention and treatment of asthma, as current therapies, which are geared towards airway inflammation and hyperreactivity, do not seem to be of benefit in the subgroup of asthmatic patients with airway remodeling who suffer from persistent symptoms and progressive decline in lung function. I have assembled a mentoring committee of nationally recognized scientists with the requisite expertise to advise me in the relevant disciplines, which, together with a focused training and research plan facilitated by a K23 research award, will help me achieve my goal of developing an independent career in clinical and translational research, focusing on questions relevant to pulmonary immunology and its role in the pathogenesis of respiratory diseases, such as asthma.